The present invention relates to devices and methods for the treatment of anorectal disorders, and more particularly to devices and methods for localized delivery of an active pharmaceutical ingredient to the anal sphincter.
Sphincters are circular groups of smooth muscle that control the orifices of hollow organs. Sphincters present throughout the gastrointestinal (GI) tract control the passage of materials through this system of the body. When constricted, the sphincters close orifices leading to the hollow organs, such as the stomach, intestine and anus. In order for the sphincter to open, the muscles must relax.
The rectum is the terminal portion of the large intestine, ending at the anal canal. The anal canal begins where the terminal portion of the large intestine passes through the pelvic floor muscles, and ends at the anal verge. The sphincter that closes the anus (sphincter ani) consists of two sphincter muscle groups. The internal anal sphincter (IAS) is a ring of smooth muscle which surrounds the lower extremity of the rectum and is formed by an aggregation of the involuntary smooth muscle fibers. The internal anal sphincter is under a state of chronic contraction, due both to intrinsic myogenic properties and external innervation. Projections from nerves within the enteric nervous system serve to control the internal anal sphincter. The external anal sphincter (EAS) is a thin flat plane of striated muscle fibers, under voluntary control, adherent to the integument surrounding the margin of the anus.
The anal sphincter keeps the anus closed as stool collects in the rectum. Eventually the pressure on the rectum wall causes the anal sphincter to relax, allowing stool to pass out of the body through the anus. Both the internal and external sphincter muscles need to relax in order to pass stool.
Anorectal disorders include anal sphincter spasm, anal fissures, abscesses, fistulae, ulcers, irritation and itching (pruritus ani), hemorrhoids, incontinence, constipation, inflammation, infection, and cancer.
Anal sphincter spasm is a condition in which the muscles of the internal anal sphincter are under abnormal tension. This may be caused, for example, by local inflammation. The strong contractions of the internal anal sphincter associated with sphincter spasm often give rise to mucosal ischaemia, resulting in anal fissures, which are painful linear ulcers or crack-like tears in the distal anal canal, which, in the short-term, usually involves only the epithelium and, in the long-term, involves the full thickness of the anal mucosa. Anal sphincter spasm can cause sharp pain, especially when opening the bowels. Anal sphincter spasm is also a cause of the pain following rectal surgery or thrombosed hemorrhoids.
Anal fissures may be also be caused by trauma from the passage of a particularly hard or painful bowel movement particularly as a result of constipation. Because of the pain of a fissure, the internal anal sphincter may go into spasm, raising pressure within the anus. This excess pressure makes it harder to pass stool, exacerbating the constipation, increasing the pressure to form a vicious circle. The spasm of the internal anal sphincter can also restrict the blood supply to the anal skin, reducing its ability to heal.
An acute anal fissure is of short duration (less than a month), and usually heals spontaneously or as a result of simple treatments such as a high fiber diet with adequate water intake or the use of bulk laxatives. Warm sitz baths may provide added symptomatic relief (Jensen, 1986). Applications of heat, cold, witch hazel, topical local anesthetics (e.g., lidocaine), topical steroids (e.g., hydrocortisone), stool softeners, and bed rest have also been prescribed to treat rectal pain.
Acute anal fissures which do not heal become chronic anal fissures or anal ulcers. Current treatments of chronic anal fissures are directed at relieving sphincter spasm and include dilatation (under anesthesia), or cutting a part of the sphincter (lateral internal sphincterotomy) to reduce the hypertonicity of the internal anal sphincter muscle. The Standards Task Force of the American Society of Colon and Rectal Surgeons recommends management of chronic anal fissures by “subcutaneous or open lateral internal sphincterotomy, posterior internal sphincterotomy with advanced flap, or manual dilatation”. Healing occurs following sphincterotomy in 95% of cases. Successful sphincterotomy (or manual dilatation) is associated with a significant decrease in intra-anal pressure. However, a number of patients experience incontinence following the surgical procedure. These and other complications have driven the search for alternative methods of reducing anal pressure. Research has been directed towards finding a means of non-surgically reducing anal pressure whilst leaving the ring of internal anal sphincter muscle intact.
Pharmacological treatments for reducing anal pressure includes administration of nitric oxide donors, botulinum toxin, muscarinic agents, sympathetic neuromodulators, and calcium channel antagonists as active pharmaceutical ingredients (APIs).
The discovery that nitric oxide is the principal non-adrenergic non-cholinergic inhibitory transmitter mediating relaxation in the internal anal sphincter led to research into exogenous organic nitrates as a source of nitric oxide, to pharmacologically manipulate the internal anal sphincter. Exogenous nitrates are degraded by cellular metabolism, releasing nitric oxide, and in vitro studies have demonstrated that topical application of ointments or pastes containing nitric oxide donors, such as nitroglycerin, glyceryl trinitrate, or isorbide dinitrate, cause a relaxation of internal anal sphincter smooth muscle (Guillemot, 1993; Lacier, 1994; Gorfine, 1995; Schouten, 1996; Carapeti, 1999), resulting in pain reduction and increased fissure healing. More recent studies have suggested that the application of the nitric oxide precursor, L-arginine, causes a reduction in resting anal pressure.
Botulinum toxin is a powerful biological toxin which binds to pre-synaptic cholinergic nerve terminals. The toxin is taken up and acts rapidly to inhibit the calcium-dependent exocytosis of acetylcholine, causing paralysis within a few hours. Neuromuscular transmission resumes after the growth of new axon terminals but clinical weakening of the muscle lasts for 3 to 4 months. Patients treated with botulinum toxin injection into the external anal sphincter showed a reduction in voluntary squeeze pressure and healing of the fissure. However, peri-anal thrombosis has been reported in some patients (Jost, 1997). Injection of botulimum toxin into the internal anal sphincter of patients with anal fissure reduced pain and promoted fissure healing (Gui, 1994).
Muscarinic agents, such as bethanecol, used as a topical cream have been found to reducing resting anal pressure and increased healing of anal fissures (Carapeti, 2000).
Use of sympathetic neuromodulators to reduce internal anal sphincter tone has also been attempted. For example, β-receptor agonist, salbutamol, administered by inhalation, and the α1-antagonist, indoramin, administered orally, have both been shown to reduce resting anal pressure in healthy controls and patients with fissures. However, the reduction has been found to be relatively low, and does not consistently lead to increased fissure healing.
Calcium is known to be important for both agonist-induced contraction of the internal anal sphincter and myogenic tone. Calcium channel antagonists, such as diltiazem have therefore been used in an attempt to modulate resting anal pressure (Jonard and Essamri). Oral diltiazem caused a reduction in resting anal pressure, but was associated with postural hypotension in a number of patients. Topical diltiazem has been shown to reduce resting anal pressure in healthy volunteers, and results in fissure healing. The topical preparation caused a greater reduction in resting anal pressure and healed more fissures with fewer side-effects (Griffin, 2002). The calcium channel blocker, nifedipine, administered as a gel, has also been shown to be effective in reduction of resting anal pressure, resulting in a decrease of anal pain associated with hypertension (Bhardwaj, 2000).
Anorectal abscesses are localized pocket of pus caused by bacterial infection. Abscesses are classified based on their anatomical location. The most commonly described locations are perianal, ischiorectal, intersphincteric, and supralevator. Perianal abscesses are located beneath the skin of the anal canal and do not transverse the external sphincter; ischiorectal abscesses form when suppuration transverses the external sphincter into the ischiorectal space; intersphincteric abscesses result from suppuration contained between the internal and external anal sphincters; and supralevator abscesses result either from suppuration extending cranially through the longitudinal muscle of the rectum from an origin in the intersphincteric space to reach above the levators, or as a result of primary disease in the pelvis (e.g., appendicitis, diverticular disease, gynecological sepsis). Certain conditions, such as Crohn's disease can increase the risk of abscess in and around the anal canal. Patients with conditions that reduce the body's immunity, such as cancer or AIDS, are also more likely to develop anal abscesses. An abscess causes tenderness, swelling, and pain. The patient may also complain of fever, chills, and general weakness or fatigue. Abscesses may be treated by drainage, or by administration of antibiotics, such as ampicillin, cefazolin, and clindamycin. Analgesics, such as meperidine, may also be prescribed.
Anal fistulae are tiny channels or tracts that develop in the presence of inflammation and infection. These may or may not be associated with an abscess, but like abscesses, certain illnesses such as Crohn's disease can cause fistulae to develop. The channel usually runs from the rectum to an opening in the skin around the anus. Treatment for fistulae varies depending on the cause and extent of the fistula, but often involves surgical intervention combined with antibiotic therapy.
Itchy skin around the anus (pruritus ani) can have many causes, including skin disorders (such as psoriasis and atopic dermatitis), diseases such as diabetes or liver disease, anal disorders (such as skin tags or draining fistulas), cancers such as Bowen's disease, allergic reactions (such as contact dermatitis caused by anesthetic preparations applied to the skin, various ointments, or chemicals used in soap), lack of hygiene or infections with fungi, bacteria, or parasites. Itching may also be a side effect of antibiotics, especially tetracycline. Treatment may comprise administration of corticosteroid creams, antifungal creams or simply washing.
The term hemorrhoids refers to a condition in which the veins around the anus or lower rectum are swollen and inflamed. Hemorrhoids may result from straining to move stool. Other contributing factors include pregnancy, aging, chronic constipation or diarrhea, and anal intercourse. Hemorrhoids occur both inside and above the anus (internal) or under the skin around the anus (external). APIs for the treatment of hemorrhoids include nitrates, such as isosorbide dinitrate (Briel, 2000), or calcium channel blockers.
Natural treatments for hemorrhoids include the use of herbs and dietary supplements that strengthen vein walls as APIs, such as butcher's broom, horse chestnut, bromelains, bioflavanoids, and Japanese pagoda tree extracts; or natural astringents and soothing agents such as witch hazel, cranesbill and aloe vera (MacKay, 2001).
Constipation and incontinence may both be caused by a combination of interrelated factors which include the sphincter muscles, rectal and anal sensation, as well as stool composition. Incontinence is associated with a reduction in anal pressure, which results principally from the activity of the anal sphincter muscles. Incontinence may be treated by APIs which enhance anal tone, such as inhibitors of nitric oxide synthase, or phenylephrine (Cook, 2001). Constipation may be treated with laxatives, such as bulk laxative, osmotic laxatives, stimulant laxatives, poorly absorbed sugars, stool softeners, enemas, cholinergic agents or prokinetic agents.
Certain APIs for the treatment of anorectal disorders, such as antibiotics, may be administered systemically, for example orally or by injection. This method is associated with a high occurrence rate of systemic side effects that limit its use, and by the potential for drug interactions with other medications prescribed to the patient. The oral route may be inefficient, with poor bioavailability of high dose or low solubility APIs, such that only part of the dose is absorbed. Due to the “first-pass” effect, APIs absorbed orally are transported to the general circulation via the liver. Thus APIs which are extensively metabolized will be metabolized in the liver during absorption. Furthermore, food and gastrointestinal motility can effect API absorption. Absorption is slower with food for tetracyclines and penicillins. Orally administered antibiotics may kill normal gut flora and allow overgrowth of fungal varieties. Thus, an antifungal agent may be required in addition to the antibiotic.
Administration by rectal injection is limited by its high cost, since these performed only by medically qualified personnel, and is reserved for APIs with long activity time (such as botulinum).
Another method of API application is by the use of suppositories. Suppositories are solid, bullet-shaped preparations designed for easy insertion into the anus. The API is incorporated into a base, which melts at body temperature and gradually spreads over the lining of the rectum.
U.S. Pat. No. 5,413,793 teaches a multiphase pharmaceutical composition for combating an anorectal disease, in which a first phase contains an active ingredient and a second phase provides a layer of silicone oil to cover the treatment area, to repel water therefrom, so protecting the area from erosion by aqueous media. This composition is in the form of a suppository, which may be provided in any standard suppository base.
Upon administration of an active pharmaceutical ingredient using a suppository, the API diffuses out of the suppository in an uncontrolled manner into the rectum. Since the rectum has a rich blood supply, the API is absorbed rapidly into the blood leading to systemic delivery of the API rather than topical delivery. For topical administration, administration via suppository is associated with a high rate of adverse effects, possible interactions with other APIs as well as variation in the bioavailability of certain APIs, in particular those which undergo extensive first-pass elimination.
For treatment of the anal sphincter, topical administration of a topical preparation directly to the rectal area is preferred. Currently known preparations are provided in the form of a powder, spray, ointment, paste, cream, lotion, gels, or solution. For example, U.S. Pat. No. 6,395,736 teaches compositions and methods for the treatment of anorectal disorders in which combinations of nitric oxide donors, phosphodiesterase inhibitors, superoxide scavengers, β-adrenergic agonists, cyclic adenosine monophosphate-dependent protein kinase activators, α1-adrenergic antagonists, L-type calcium channel blockers, estrogens, adenosine triphosphate-sensitive calcium channel activators and smooth muscle relaxants are used. These are administered by any of the standard dosage forms listed above.
The prior art dosage forms for direct topical application for the treatment of anorectal disorders, such as powders, sprays, ointments, pastes, creams, lotions, gels, and solutions are messy and inconvenient to use. Application of the composition several times daily is required, which is inconvenient and disruptive to daily activities, and may reduce patient compliance. Another problem associated with direct topical application is the possible soiling of clothes, that might affect social activity.
The prior art does not teach or suggest methods or devices for convenient, highly localized delivery of APIs to the anal sphincter.